Orofacial clefts, cleft with without cleft (CLIP), health problem, affecting one in every 500-1000 births worldwide. There has been substantial recent progress by our group and others in identifying genetic loci for CL/P, confirming the suspected complexity in the genetic etiology of CL/P. As the genetic factors contributing to CLIP emerge, it is essential to identify the phenotypic characteristics attributable to each gene n order to translate the emerg ng research results into cinical practice. Progress has also been made regarding phenotypic features associated with CLIP: there is evidence that developmental asymmetry effects may contribute to the etiology of CLIP, and that there may be unrecognized sub-clinical phenotypes in apparently unaffected relatives of individuals with clefts. The primary goal of this study is to utilize an expanded phenotypic spectrum for CLIP in our linkage and association studies of candidate genes, genome-scan and fine-mapping markers. An expanded phenotypic spectrum for CLIP will more accurately identify the phenotype that is segregating at a genetic level in specific cleft families, thereby increasing the power of our gene mapping and association studies. Furthermore, if we can then identify unaffected (i.e. non-cleft) individuals who are likely to be carrying cleft genes (e.g. individuals with sub-clinical phenotypic expression), then recurrence risk calculations and genetic counseling for this common birth defect will be vastly improved. Therefore, we will investigate phenotypic features in multiplex kindreds (i.e. with 2 or more affecteds) ascertained through CL/P individuals, plus controls, in several populations world-wide. The specific features that will be investigated include: handedness, craniofacial measurements, asymmetry (based on dermatoglyphic patterns and craniofacial measurements), velopharyngeal competence (by perceptual screening) and anatomy of the orbicularis oris muscle. Each individual feature will be analyzed, as well as composite traits composed of two or more features. Candidate genes will be prioritized in collaboration with the other Center Projects; candidate genes will be genotyped utilizing the Genotype Core. Genome-scan markers are already available for most of these families. All markers will be used for linkage and association studies of CLIP and each phenotypic feature in the multiplex kindreds, and will also be included in analyses looking for interactions between genes contributing to risk.